In this four year clinical trial submission, he will test two hypotheses based on pre-clinical data from the Pi's and the co-investigator's labs that: 1. treatment of human dendritic cells (DC) derived from peripheral blood monocytes with CD40 ligand (CD4oL) will induce DC maturation, provide T-cell helper signals and augment the ability of DC to achieve clinical anti-tumor and immune responses in patients with metastatic melanoma; 2. treatment of patients receiving peptide-pulsed DC with IL-2 will augment the clinical activity and immunogenicity of the DC. Patients with metastatic melanoma that are HLA-A2 positive will be treated with autologous DC pulsed with peptides derived from three tumor antigens. The MART-1 27-35, gp100 209-217 (210M) and tyrosinase 368-376 (370D) peptides will be pulsed onto DC derived from ficolled PBMC treated with GM-CSF and IL-4. Patients will be treated on successive phase II trials with a two-part Simon design. In an initial trial 21 patients will be treated intravenously with DC treated with a preparation of helper peptides and IL-4/GM-CSF to which CD40 ligand/gamma interferon are added. If 2 or more responses are seen then a further 20 patients will be added to the initial trial. If 5 or more responses of 41 are observed, then the DC regimen will be felt worthy of further study and a second phase II study will be performed with IL-2 therapy added to the DC regimen. The principal endpoint of the phase II trials to be conducted as a collaboration between USC/Norris Cancer Center and the University of Michigan Cancer Center is the achievement of objective clinical responses. As a secondary endpoint, immune responses will be assessed by detection of cytokine release from peripheral blood T cells restimulated with epitope peptides in ELISA or ELISPOT assays, and by flow cytometric detection of peptide specific T cells using MHC class I tetramers bound to specific peptides. Patients will receive one hundred million DC every two weeks for three infusions. Patients in the 2nd trial receiving IL-2 SC will be treated daily for 5 days after each DC infusion. Leucopheresis will be performed to obtain PBMC for production of DC and to cryopreserve PBMC for immune assays. Four weeks after 3 infusions of DC, another pheresis will be performed to cryopreserve PBMC for post-treatment immune assays, and to provide DC for a second treatment cycle if there is disease stability or regression. The goal of this proposal is to develop an "optimum" regimen for DC therapy by provision of maturation and T-helper signals through CD40 ligand and IL-2 pathways that are necessary for generation of strong CTL responses by DC grown in IL-4 and GM-CSF and pulsed with class I restricted epitope peptides.